Insights into the evolution of the ErbB receptor family and their ligands from sequence analysis

BACKGROUND: In the time since we presented the first molecular evolutionary study of the ErbB family of receptors and the EGF family of ligands, there has been a dramatic increase in genomic sequences available. We have utilized this greatly expanded data set in this study of the ErbB family of receptors and their ligands. RESULTS: In our previous analysis we postulated that EGF family ligands could be characterized by the presence of a splice site in the coding region between the fourth and fifth cysteines of the EGF module and the placement of that module near the transmembrane domain. The recent identification of several new ligands for the ErbB receptors supports this characterization of an ErbB ligand; further, applying this characterization to available sequences suggests additional potential ligands for these receptors, the EGF modules from previously identified proteins: interphotoreceptor matrix proteoglycan-2, the alpha and beta subunit of meprin A, and mucins 3, 4, 12, and 17. The newly available sequences have caused some reorganizations of relationships among the ErbB ligand family, but they add support to the previous conclusion that three gene duplication events gave rise to the present family of four ErbB receptors among the tetrapods. CONCLUSION: This study provides strong support for the hypothesis that the presence of an easily identifiable sequence motif can distinguish EGF family ligands from other EGF-like modules and reveals several potential new EGF family ligands. It also raises interesting questions about the evolution of ErbB2 and ErbB3: Does ErbB2 in teleosts function differently from ErbB2 in tetrapods in terms of ligand binding and intramolecular tethering? When did ErbB3 lose kinase activity, and what is the functional significance of the divergence of its kinase domain among teleosts

Dimensionality dependent electronic structure of the exfoliated van der Waals antiferromagnet NiPS3_3

Resonant Inelastic X-ray Scattering (RIXS) was used to measure the local electronic structure in few-layer exfoliated flakes of the van der Waals antiferromagnet NiPS$_3$. The resulting spectra show a systematic softening and broadening of $NiS_6$ multiplet excitations with decreasing layer count from the bulk to three atomic layers (3L). These trends are driven by a decrease in the transition metal-ligand and ligand-ligand hopping integrals, and in the charge-transfer energy: $\Delta$ = 0.60 eV in the bulk and 0.22 eV in 3L NiPS$_3$. Relevant intralayer magnetic exchange integrals computed from the electronic parameters exhibit a systematic decrease in the average interaction strength with thickness and place 2D NiPS$_3$ close to the phase boundary between stripy and spiral antiferromagnetic order, which may explain the apparent vanishing of long-range order in the 2D limit. This study explicitly demonstrates the influence of $inter$layer electronic interactions on $intra$layer ones in insulating magnets. As a consequence, the magnetic Hamiltonian in few-layer insulating magnets can be significantly different from that in the bulk.Comment: 5 pages, 4 figures; additional 9 pages and 13 figures of supplementary informatio

Targeted LC–MS derivatization for aldehydes and carboxylic acids with a new derivatization agent 4-APEBA

Based on the template of a recently introduced derivatization reagent for aldehydes, 4-(2-(trimethylammonio)ethoxy)benzeneaminium dibromide (4-APC), a new derivatization agent was designed with additional features for the analysis and screening of biomarkers of lipid peroxidation. The new derivatization reagent, 4-(2-((4-bromophenethyl)dimethylammonio)ethoxy)benzenaminium dibromide (4-APEBA) contains a bromophenethyl group to incorporate an isotopic signature to the derivatives and to add additional fragmentation identifiers, collectively enhancing the abilities for detection and screening of unknown aldehydes. Derivatization can be achieved under mild conditions (pH 5.7, 10 °C). By changing the secondary reagent (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide instead of sodium cyanoborohydride), 4-APEBA is also applicable to the selective derivatization of carboxylic acids. Synthesis of the new label, exploration of the derivatization conditions, characterization of the fragmentation of the aldehyde and carboxylic acid derivatives in MS/MS, and preliminary applications of the labeling strategy for the analysis of aldehydes in urine and plasma are described

Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life.

BACKGROUND: Factors driving inter-individual differences in immune responses upon different types of prenatal malaria exposure (PME) and subsequent risk of malaria in infancy remain poorly understood. In this study, we examined the impact of four types of PME (i.e., maternal peripheral infection and placental acute, chronic, and past infections) on both spontaneous and toll-like receptors (TLRs)-mediated cytokine production in cord blood and how these innate immune responses modulate the risk of malaria during the first year of life. METHODS: We conducted a birth cohort study of 313 mother-child pairs nested within the COSMIC clinical trial (NCT01941264), which was assessing malaria preventive interventions during pregnancy in Burkina Faso. Malaria infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. Supernatant concentrations of 30 cytokines, chemokines, and growth factors induced by stimulation of cord blood with agonists of TLRs 3, 7/8, and 9 were measured by quantitative suspension array technology. Crude concentrations and ratios of TLR-mediated cytokine responses relative to background control were analyzed. RESULTS: Spontaneous production of innate immune biomarkers was significantly reduced in cord blood of infants exposed to malaria, with variation among PME groups, as compared to those from the non-exposed control group. However, following TLR7/8 stimulation, which showed higher induction of cytokines/chemokines/growth factors than TLRs 3 and 9, cord blood cells of infants with evidence of past placental malaria were hyper-responsive in comparison to those of infants not-exposed. In addition, certain biomarkers, which levels were significantly modified depending on the PME category, were independent predictors of either malaria risk (GM-CSF TLR7/8 crude) or protection (IL-12 TLR7/8 ratio and IP-10 TLR3 crude, IL-1RA TLR7/8 ratio) during the first year of life. CONCLUSIONS: These findings indicate that past placental malaria has a profound effect on fetal immune system and that the differential alterations of innate immune responses by PME categories might drive heterogeneity between individuals to clinical malaria susceptibility during the first year of life

Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis

<p>Abstract</p> <p>Objective</p> <p>Cytokines play important roles in mediating inflammation in autoimmunity. Several cytokines are elevated in serum and synovial fluid samples from children with Juvenile Idiopathic Arthritis (JIA). Soluble CD154 (sCD154) is elevated in other autoimmune disorders, but has not been characterized in JIA. Our objectives were to determine if sCD154 is elevated in JIA, and to examine correlations between sCD154 and other inflammatory cytokines.</p> <p>Methods</p> <p>Serum from 77 children with JIA and 81 pediatric controls was analyzed for interleukin (IL)1β, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, sCD154, interferon-γ (IFNγ), soluble IL2 receptor (sIL2R), and tumor necrosis factor-α (TNFα), using the Luminex Multi-Analyte Profiling system. Differences in levels of cytokines between cases and controls were analyzed. Logistic regression was also performed.</p> <p>Results</p> <p>sCD154 was significantly elevated in cases compared to controls (p < 0.0001). IL1β, IL5, IL6, IL8, IL13, IFNγ, sIL2R, and TNFα were also significantly elevated in JIA. Levels of sCD154 were highly correlated with IL1β, IL6, IL8, and TNFα (p < 0.0001). Logistic regression analysis suggested that IL6 (odds ratio (OR): 1.4, p < 0.0001), sCD154 (OR: 1.1, p < 0.0001), and TNFα (OR: 1.1, p < 0.005) were positively associated with JIA, while IL10 (OR: 0.5, p < 0.002) was protective. sCD154 was elevated in all JIA subtypes, with highest levels among more severe subtypes. IL1β, IL6, IL8, sIL2R and TNFα were also elevated in several JIA subtypes.</p> <p>Conclusion</p> <p>Serum levels of sCD154, IL1β, IL6, IL8, sIL2R and TNFα are elevated in most JIA subtypes, suggesting a major role for sCD154, and these cytokines and cytokine receptors in the pathogenesis of JIA.</p